Balamurugan Kuppusamy, Hua Haiqing, Georgiev Oleg, Schaffner Walter
Institute of Molecular Biology, University of Zurich, Winterthurer Str. 190, CH-8057 Zurich, Switzerland.
Biol Chem. 2009 Feb;390(2):109-13. doi: 10.1515/BC.2009.020.
Organisms from insects to mammals respond to heavy metal load (copper, zinc, cadmium, and mercury) by activating the metal-responsive transcription factor 1 (MTF-1). MTF-1 binds to short DNA sequence motifs, termed metal response elements, and boosts transcription of a number of genes, notably those for metallothioneins. In Drosophila, MTF-1 somewhat counter-intuitively also activates transcription of a copper importer gene (Ctr1B) in response to copper starvation. Here, we report that mutant flies lacking Ctr1B are extremely sensitive to cadmium and mercury treatment, but can be rescued by excess copper in the food. We thus propose that copper, by competing for binding sites on cellular proteins, alleviates the toxic effects of mercury and cadmium. Such a scenario also explains a seemingly fortuitous metal response, namely, that cadmium and mercury strongly induce the expression of a Ctr1B reporter gene. Thus, the transcription enhancer/promoter region of the Ctr1B copper importer gene is subject to three modes of regulation. All of them depend on MTF-1 and all make biological sense, namely, (i) induction by copper starvation, (ii) repression by copper abundance, and (iii), as shown here, induction by cadmium or mercury at normal copper supply.
从昆虫到哺乳动物，生物体通过激活金属反应转录因子1（MTF-1）来应对重金属负荷（铜、锌、镉和汞）。MTF-1与称为金属反应元件的短DNA序列基序结合，并促进许多基因的转录，特别是金属硫蛋白的基因。在果蝇中，MTF-1在应对铜饥饿时还会激活一个铜转运蛋白基因（Ctr1B）的转录，这有点违反直觉。在这里，我们报告缺乏Ctr1B的突变果蝇对镉和汞处理极其敏感，但食物中的过量铜可以挽救它们。因此，我们提出铜通过竞争细胞蛋白质上的结合位点，减轻了汞和镉的毒性作用。这种情况也解释了一种看似偶然的金属反应，即镉和汞强烈诱导Ctr1B报告基因的表达。因此，Ctr1B铜转运蛋白基因的转录增强子/启动子区域受到三种调控模式的影响。所有这些都依赖于MTF-1，并且都具有生物学意义，即：（i）铜饥饿诱导，（ii）铜充足时抑制，以及（iii）如本文所示，正常铜供应时镉或汞诱导。
